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Comparative Burden of Subclinical Tremor in a Cohort of Normal Individuals Stratified by Familial Risk for Essential Tremor.

ABSTRACT: BACKGROUND:The burden of mild (i.e., subclinical) tremor within essential tremor (ET) families is not fully understood. We assessed the burden of mild tremor in a cohort of 287 adults, none of whom reported tremor or were diagnosed with ET. METHODS:We recruited adults in 2 groups based on the familial risk for ET: 244 high-risk individuals (i.e., reporting one or more first-degree relative with ET) and 43 low-risk individuals (i.e., reporting no relatives with ET). Tremor was objectively assessed on 4 hand-drawn spirals (total spiral score = 0-12). Mild tremor was defined using 3 different cut points. RESULTS:The prevalence rates of mild tremor among high-risk individuals ranged from 41.4 to 98.4% and were highly dependent on the cut point. Above a certain threshold (i.e., a total spiral score ?5), 1-in-5 (i.e., 19.7%) high-risk individuals exhibited mild tremor, whereas no low-risk individuals did. High-risk individuals were 3.09-4.50 times more likely than low-risk individuals to exhibit mild tremor. CONCLUSION:The burden of ET extends beyond the boundaries of the clinically defined disease, and partially expressed forms of ET are abundant in ET families. This fact greatly complicates gene-finding studies and epidemiological studies whose goal is to detect disease-linked associations.

SUBMITTER: Louis ED

PROVIDER: S-EPMC5860954 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Comparative Burden of Subclinical Tremor in a Cohort of Normal Individuals Stratified by Familial Risk for Essential Tremor.

Louis Elan D ED Meyers James H JH Badejo Olufunmilayo M OM Cristal Ashley D AD Hickman Ruby R Factor-Litvak Pam P

Neuroepidemiology 20180116 1-2

<h4>Background</h4>The burden of mild (i.e., subclinical) tremor within essential tremor (ET) families is not fully understood. We assessed the burden of mild tremor in a cohort of 287 adults, none of whom reported tremor or were diagnosed with ET.<h4>Methods</h4>We recruited adults in 2 groups based on the familial risk for ET: 244 high-risk individuals (i.e., reporting one or more first-degree relative with ET) and 43 low-risk individuals (i.e., reporting no relatives with ET). Tremor was obje ...[more]

PMID: 29339654

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Project description:Background Essential tremor (ET) is among the most common movement disorders in adults. While ET is diagnosed and primarily characterized by the presence of tremor, it also can impact cognition, sleep, mood, and motor functioning more broadly. The manifestations of ET can have various consequences, including difficulty with activities of daily living (ADL), embarrassment, and overall decline in health-related quality of life, which have not been fully explored in prior studies. Objective We performed a systematic literature review to comprehensively characterize the burden experienced by patients with ET from the clinical and humanistic perspectives, focusing on outcomes beyond tremor. Methods This systematic literature review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches in PubMed, Embase, and Cochrane Library identified original, observational studies of the clinical and humanistic burden in adult patients with ET published in English between 2010 and 2020. Studies assessing epidemiology, treatment patterns, or disease management were excluded. Search results were screened according to pre-determined eligibility criteria. Data from included studies were collected, independently verified, and qualitatively synthesized. Results Following the screening of 2,303 records and 145 full-text articles, 39 studies were identified. There was significant heterogeneity in study designs, statistical approaches, and patient cohorts across the included studies. Patients with ET in these studies exhibited more severe disabilities and reduced independence compared to healthy individuals, and they often struggled to perform ADL and relied on caregivers for physical and emotional support. Patients also experienced various issues with movement and balance, increased risk of falls, depression, anxiety, poor sleep quality, and psychosocial consequences including embarrassment, apathy, and enfeeblement. Conclusion A systematic literature review of non-tremor manifestations and/or consequences of ET identified far-reaching negative impacts on patients' ability to function independently and revealed accompanying psychosocial effects, including social fear and embarrassment. The reduced function and psychosocial deficits observed in patients with ET result in significant clinical and humanistic burdens, decreasing quality of life. Future studies should evaluate this condition beyond the tremor itself to provide an improved understanding of the multi-dimensional burden of the disease, thereby highlighting the need to diagnose and appropriately manage patients with ET.

Project description:BackgroundEssential tremor (ET), one of the most common neurological disorders, has a phenotypically heterogeneous presentation characterized by bilateral kinetic tremor of the arms and, in some patients, tremor involving other body regions (e.g., head, voice). Genetic studies suggest that ET is genetically heterogeneous.MethodsWe analyzed whole genome sequence data (WGS) generated on 104 multi-generational white families with European ancestry affected by ET. Genome-wide parametric linkage and association scans were analyzed using adjusted logistic regression models through the application of the Pseudomarker software. To investigate the additional contribution of rare variants in familial ET, we also performed an aggregate variant non-parametric linkage (NPL) analysis using the collapsed haplotype method implemented in CHP-NPL software.FindingsParametric linkage analysis of common variants identified several loci with significant evidence of linkage (HLOD ≥3.6). Among the gene regions within the strongest ET linkage peaks were BTC (4q13.3, HLOD=4.53), N6AMT1 (21q21.3, HLOD=4.31), PCDH9 (13q21.32, HLOD=4.21), EYA1 (8q13.3, HLOD=4.04), RBFOX1 (16p13.3, HLOD=4.02), MAPT (17q21.31, HLOD=3.99) and SCARB2 (4q21.1, HLOD=3.65). CHP-NPL analysis identified fifteen additional genes with evidence of significant linkage (LOD ≥3.8). These genes include TUBB2A, VPS33B, STEAP1B, SPINK5, ZRANB1, TBC1D3C, PDPR, NPY4R, ETS2, ZNF736, SPATA21, ARL17A, PZP, BLK and CCDC94. In one ET family contributing to the linkage peak on chromosome 16p13.3, we identified a likely pathogenic heterozygous canonical splice acceptor variant in exon 2 of RBFOX1 (ENST00000547372; c.4-2A>G), that co-segregated with the ET phenotype in the family.InterpretationLinkage and association analyses of WGS identified several novel ET candidate genes, which are implicated in four major pathways that include 1) the epidermal growth factor receptor-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha-AKT serine/threonine kinase 1 (EGFR-PI3K-AKT) and Mitogen-activated protein Kinase 1 (ERK) pathways, 2) Reactive oxygen species (ROS) and DNA repair, 3) gamma-aminobutyric acid-ergic (GABAergic) system and 4) RNA binding and regulation of RNA processes. Our study provides evidence for a possible overlap in the genetic architecture of ET, neurological disease, cancer and aging. The genes and pathways identified can be prioritized in future genetic and functional studies.FundingNational Institutes of Health, NINDS, NS073872 (USA) and NIA AG058131(USA).

Dataset Information

Comparative Burden of Subclinical Tremor in a Cohort of Normal Individuals Stratified by Familial Risk for Essential Tremor.

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Comparative Burden of Subclinical Tremor in a Cohort of Normal Individuals Stratified by Familial Risk for Essential Tremor.

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